Molecular bases of the regulation of energy expenditure by bone

PROJECT SUMMARY-Project #4 The bone-derived hormone osteocalcin (OCN) is released during bone remodeling, a process that declines with age. Physiological functions regulated by OCN, such as fertility, glucose tolerance, and cognition, deteriorate over the lifespan in parallel with circulating levels of the active form of OCN. Here we explore the possibility that OCN regulates another age-dependent process, thermogenesis, through effects on brown adipose tissue (BAT). We consider two types of thermoregulatory dysfunction in aging populations: cold intolerance and hot flashes. BAT is a thermogenic organ that oxidizes fatty acids and glucose to produce heat. Cold or pharmacological stimulation of BAT induces thermogenesis and improves glucose tolerance in mice and humans. Aging is associated with diminished BAT function and increased risks of hypothermia and metabolic dysfunction. Little is known about the causes and consequences of impaired BAT function in aging because most studies in animal models exclusively evaluate young adults. Sympathetic nervous system (SNS) tone, the primary driver of BAT activity, is elevated in aged individuals. Thus, reduced BAT activity in aging reflects hyporesponsiveness to cold and SNS signaling. Factors that can enhance sensitivity to SNS signals or regulate BAT function independent of the SNS have the potential to improve metabolic and thermoregulatory dysfunction that accompanies aging. OCN levels decrease in aging, in parallel with reduced responsiveness of BAT to cold and sympathetic signaling. Conversely, OCN treatment is sufficient to stimulate a thermogenic gene program in brown adipocytes in vitro and to protect against diet-induced obesity (DIO) by increasing energy expenditure and BAT capacity in vivo. Studies in Aim 1 will explore whether loss of endogenous OCN increases susceptibility to cold and DIO via diminished BAT function in Ocn-/- mutants and aged wild-type mice. Studies in Aim 2 will investigate the mechanism by which exogenous OCN protects against DIO and ask whether restoring physiological levels of OCN to aged mice will improve metabolic function and cold tolerance by activating BAT. Studies in Aim 3 will consider another situation where OCN and thermoregulation are dysregulated, peri-menopausal hot flashes. Estrogen depletion in the peri-menopausal period or following ovariectomy is associated with a burst of bone resorption and a transient increase in active OCN levels. This period is often accompanied by thermal dysregulation and vasomotor symptoms (VMS) in the form of hot flashes. Conditions associated with reduced bone absorption and OCN, including treatment with anti-resorptive compounds and obesity, are associated with reduced risk of hot flashes. We will investigate the role of OCN in a mouse model of hot flashes. If successful, this research will provide novel insights into the mechanism underlying sensitivity to cold and DIO in aged individuals and hot flashes in peri-menopausal women understudied issues with widespread effects.